Oral Administration as a Potential Alternative for the Delivery of Small Extracellular Vesicles
Abstract
:1. Introduction
2. Challenges of Orally Administered sEVs
3. Biodistribution, Stability, and Safety of Oral Delivery of Native and Drug Loaded sEVs
4. sEVs Attributes for an Efficient Oral Administration
5. Cellular and Molecular Mediators for sEVs Uptake after Oral Administration
6. Food Derived Vesicles (FDVs)-Based Nutraceutical Perspectives in Infant and Elderly Health
7. Limitation, Future Direction and Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Type of sEV | Cell Source | Labeling Method | Dose | Mouse Strain | Time of Detection and Tissue Distribution | Reference |
---|---|---|---|---|---|---|
sEVs | Bovine milk | DiR | 0.5 mg prot/mouse | C57BL/6 mice with DSS-induced ulcerative colitis | 1 h Small intestine 6 h Colon | [27] |
Exosomes | Bovine milk | DiR | 1 × 1012 part/gr of mouse | Balb/c mice | 24 h Intestine, lung, and liver | [30] |
Exosomes | Bovine milk | DiR | 40 mg prot/kg of mouse | Balb/c mice | 30 min Blood 6 h Liver, spleen, kidney, heart, and lung | [29] |
iRGD-Exosomes | Bovine milk | DiR | 40 mg prot/kg of mouse | Tumor-bearing Balb/c mice | 4 h Tumor, liver, spleen, kidney, lung, and heart | [29] |
Exosomes | Bovine milk | DiR | 60 mg prot/kg of mouse | Athymic nude mice | 4 d Liver, lung, kidney, pancreas, spleen, ovaries, colon, and brain | [31] |
sEVs | Bovine milk | DiR | 25 mg prot/kg of mouse | Balb/c mice | 2 and 6 h Intestine 24 h GI tract, liver, spleen, lungs, kidney, and heart | [28] |
sEVs | Bovine milk | DiR | 25 mg prot/kg of mouse/day × 38 days | Balb/c-Fox1nuAusb mice | 24 h Tumor tissue | [28] |
sEVs | Yeast | DiR | 25 mg prot/kg of mouse | Not indicated | 24 h GI tract, liver, spleen, kidney, lungs, and heart | [28] |
sEVs | Beer | DiR | Not indicated | Not indicated | Not bioavailable in the mice | [28] |
Exosomes-like | Grape | DiR, PKH26 | 1 mg/mouse | C57BL/6 mice | 6 h Intestine | [34] |
Exosomes-like | Acerola | PKH26 | 3 × 109 particles/mouse | C57BL/6 mice | 1 h Intestine, liver, and bladder, weak signal in brain | [33] |
Exosomes-like | Ginger | DiR | 0.3 mg/mouse | C57BL/6 mice | 12 h Colon (in non-starved mice); 12 h Stomach and small intestine (in starved mice) | [32] |
Exosomes-like | Garlic | DiR PKH26 | 1 × 1010 particles/mouse | C57BL/6 mice | 24 h Brain, liver, small intestine, and large intestine | [35] |
Exosomes-like | Tea leaves | DiR | 3 mg/kg of mouse | Balb/c mice | 6 h Small intestine | [36] |
Exosomes-like | Mulberry bark | DiR | 10 × 1010 particles/mouse | C57BL/6 mice | 3 h Small intestine, colon, cecum; small fraction was observed in spleen, liver, lung, kidney, heart, and blood | [37] |
sEVs Type and Cell Source | Dose | Murine Strain | Time of Detection | Toxicity Profile | Reference |
---|---|---|---|---|---|
Cow’s milk-derived exosomes | 25 mg/kg (single administration) 25 mg/kg daily × 15 d | Sprague Dawley rats | 6 h 15 d | No changes in clinical signs, body weight, or dietary intake in animals. Biochemical (liver and kidney function) and hematological parameters remained unchanged except for triglycerides. No changes in cytokine profile (IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, GM-CSF, IFN-γ and TNF-α), except for the anti-inflammatory cytokine GM-CSF. | [31] |
Cow’s milk-derived sEVs | 2 mg/kg × 7 d | IRC mice | 7 d | No changes in body weight in animals. Biochemical (liver function) and hematological parameters remained unchanged. Histopathology examination (H&E staining) of the heart, liver, spleen, lung, kidney, and small intestine exhibited no pathological changes. | [25] |
sEV Source | sEV Attribute/Modification/Treatment | Loaded Molecule | Biological Effect | Type of Study | References | |
---|---|---|---|---|---|---|
sEVs protection in transit trough digestive tract | Bovine milk and colorectal cancer cells | Calcium chloride addition | N/A | Enhanced EV stability after acidification (pH = 2) and boiling (105 °C) | In vitro | [28] |
Human cardiosphere-derived stromal cells | Casein addition | N/A | Enhanced uptake and disease-modifying bioactivity | In vivo | [43] | |
sEVs uptake by gut cells | Grape juice | Phosphatidic acids, Phosphatidylethanolamines | N/A | Dextrane sulfate sodium-induced colitis protection via induction of intestinal stem cells | In vivo | [34] |
sEVs targeting beyond gut mucosa | Bovine milk | Non modified | N/A | Tumor growth reduction and accelerated metastasis, xenograft | In vivo | [28] |
Bovine milk | Folic acid functionalization | Withaferin A Anthocyanidins Curcumin Paclitaxel Docetxel | Tumor targeting, xenograft | In vivo | [31] | |
Human umbilical cord | Non modified | N/A | Antioxidant and anti-apoptotic and rescue from liver failure | In vivo | [44] | |
Human MSC544 cell line | Non modified | Taxol | Tumor reducing capabilities | In vivo | [45] | |
Mouse suppresor T cells | Antibodies free light chains coating | miRNA-150 | Immune tolerance | In vivo | [46] |
Cell Lineage | Target Cell Source | sEV Source | Findings | Type of Study | References |
---|---|---|---|---|---|
Microfold cells (M cells) | Several sources | N/A (Synthetic nanoparticles) | M cells possess reduced intracellular enzymatic activity, thinner mucus layer and glycocalyx, promoting easier access and intracellular transport. | In vitro In vivo | [1] |
Macrophages | Ag-presenting macrophages | Ts cell-derived | Macrophage clodronate depletion abolishes anti-inflammatory effect of Ts derived sEVs observed in DTH model. | In vivo | [48] |
Dendritic cells | Transgenic reporter mice | M cell-derived vesicles | M cell-derived vesicles are taken up by dendritic cells. | In vivo | [58] |
Enterocytes | Rat intestinal epithelial cells (IEC-6) | Grapefruit juice | Plant EV’s miRNAs are taken up by rat intestinal enterocytes. | In vitro | [59] |
Colonocytes | Human colonocyte cell line (DLD-1) Mouse intestinal epithelial cell line (CMT-93) | Colonic luminal fluid aspirates | sEVs mRNA was present within cells, showing take up. | In vitro | [60] |
Enterocytes | Porcine intestinal cells (IPEC-J2) | Porcine milk | sEVs promoted enterocytes proliferation in vitro. increased villus height, crypt depth and ratio of villus length to crypt depth of intestinal tissues was observed in vivo. | In vitro In vivo | [61] |
Enterocytes | Rat intestinal epithelial cells (IEC-6) Human colon carcinoma (Caco-2) | Bovine milk | sEVs uptake decreased when incubated at low temperature (4 °C), after proteinase K treatment, using endocytosis inhibitors or carbohydrate competitors. | In vitro | [38] |
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Donoso-Meneses, D.; Figueroa-Valdés, A.I.; Khoury, M.; Alcayaga-Miranda, F. Oral Administration as a Potential Alternative for the Delivery of Small Extracellular Vesicles. Pharmaceutics 2023, 15, 716. https://doi.org/10.3390/pharmaceutics15030716
Donoso-Meneses D, Figueroa-Valdés AI, Khoury M, Alcayaga-Miranda F. Oral Administration as a Potential Alternative for the Delivery of Small Extracellular Vesicles. Pharmaceutics. 2023; 15(3):716. https://doi.org/10.3390/pharmaceutics15030716
Chicago/Turabian StyleDonoso-Meneses, Darío, Aliosha I. Figueroa-Valdés, Maroun Khoury, and Francisca Alcayaga-Miranda. 2023. "Oral Administration as a Potential Alternative for the Delivery of Small Extracellular Vesicles" Pharmaceutics 15, no. 3: 716. https://doi.org/10.3390/pharmaceutics15030716
APA StyleDonoso-Meneses, D., Figueroa-Valdés, A. I., Khoury, M., & Alcayaga-Miranda, F. (2023). Oral Administration as a Potential Alternative for the Delivery of Small Extracellular Vesicles. Pharmaceutics, 15(3), 716. https://doi.org/10.3390/pharmaceutics15030716